Abstract
Microsatellite instability (MSI), the spontaneous loss or gain of nucleotides from repetitive DNA tracts, is a diagnostic phenotype for gastrointestinal, endometrial, colorectal, and bladder cancers; yet a landscape of instability events across a wider variety of cancer types is beginning to be discovered. The epigenetic inactivation of the MLH1 gene is often associated with sporadic MSI cancers. Recent next-generation sequencing (NGS)-based analyses have comprehensively characterized MSI-positive (MSI+) cancers, and several approaches to the detection of the MSI phenotype of tumors using NGS have been developed. Bladder cancer (here we refer to transitional carcinoma of the bladder) is a major cause of morbidity and mortality in the Western world. Cystoscopy, a gold standard for the detection of bladder cancer, is invasive and sometimes carries unwanted complications, while its cost is relatively high. Urine cytology is of limited value due to its low sensitivity, particularly to low-grade tumors. Therefore, over the last two decades, several new “molecular assays” for the diagnosis of urothelial cancer have been developed. Here, we provide an update on the development of a microsatellite instability assay (MSA) and the development of MSA associated with bladder cancers, focusing on findings obtained from urine analysis from bladder cancer patients as compared with individuals without bladder cancer. In our review, based on over 18 publications with approximately 900 sample cohorts, we provide the sensitivity (87% to 90%) and specificity (94% to 98%) of MSA. We also provide a comparative analysis between MSA and other assays, as well as discussing the details of four different FDA-approved assays. We conclude that MSA is a potentially powerful test for bladder cancer detection and may improve the quality of life of bladder cancer patients.
Highlights
Microsatellite instability (MSI) is a molecular tumor phenotype resulting from genomic hypermutability and is initially described as variations in the length of microsatellite sequences in the entire genomic structure
Since its initial discovery, MSI has been acknowledged as a generalized phenomenon in a wide spectrum of sporadic cancers [4–8], and the underlying mechanisms for these cases of sporadic cancers seem to be based on epigenetic mechanisms, namely the methylation of
MSI detection methods have constantly changed through the pursuit of better accuracy and efficiency, which rely on the amplification of one or several microsatellite markers with polymerase chain reaction (PCR) and the detection of MSI (Figure 2)
Summary
Microsatellite instability (MSI) is a molecular tumor phenotype resulting from genomic hypermutability and is initially described as variations in the length of microsatellite sequences in the entire genomic structure. Several groups have developed methods to analyze MSI using massively parallel DNA-sequencing technologies [11–16] This new approach is based on a large number of samples but is designed to offer robust quality and quantitative precision that was not previously achievable using the PCR technique. Cancer Genome Atlas (TCGA) made it possible to predict MSI status regardless of cancer through information from tumor exomes sequencing. This approach resulted in a more comprehensive understanding of genomewide MSI [13]. LOH is typically identified by comparing the DNA isolated from tumors to normal DNA, such as that isolated from blood [7–9] This LOH can be detected using a method known as microsatellite instability analysis (MSA).
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